Melphalan is the L form of 4-(bis(2-chloroethyl)amino) phenylalanine known to exhibit antitumor activity. The D form or the racemic DL form is found to be less active than the L-form.
Invention of the molecule Melphalan was disclosed in U.S. Pat. No. 3,032,584 (Franz) and U.S. Pat. No. 3,032,585 (John) issued in 1962.
Melphalan is synthesized from a key intermediate, 4-aminophenylalanine, which is prepared from L-phenylalanine. A general synthetic scheme of the synthesis of melphalan is shown in FIG. 1.
The key intermediate 4-aminophenylalanine has two active amino groups, one at the alpha carbon to the carboxylic acid function (glycinic amino group) and the other at the 4th carbon of the phenyl ring (aromatic amino group). All the prior art processes disclose the need to protect the glycinic amino group so as to selectively introduce the hydroxyethyl or chloroethyl group on to the aromatic amino group. The protecting groups commonly used in the prior art are acetyl, formyl, and phthaloyl groups.
British patent GB1377336 discloses a process of obtaining pure L-form of 4-(bis(2-chloroethyl)amino)phenylalanine by optically resolving the DL-racemic form of the N-formyl derivative using brucine salt formation and then deprotecting the formyl group.
U.S. Pat. Nos. 3,032,584 and 3,032,585 disclose the use of having a phthaloyl group protect the glycinic amino group.
European patent EP0233733 discloses a process of making L-4-(bis(2-chloroethyl)amino) phenylalanine by using a phthalamide group to protect the glycinic amino group of a 4-nitro phenylalanine ethyl ester, and claiming an advantage over the processes disclosed in U.S. Pat. Nos. 3,032,584 and 3,032,585. This publication also discloses that a p-nitro-phthaloyl-protected intermediate (or its ethyl ester) helps in retention of optical purity.
All of the prior art examples, in one way or another, utilize a process that requires protecting the glycinic amino group to introduce the hydroxyethyl group at the aromatic amino group. In such a process, it is essential to decouple the protecting group at the end stage of the manufacturing process, which often involves aqueous hydrolysis and the encumbent generation of hydrolytic impurities which are difficult to remove. Another problem is that N-protected phenylalanine tends to racemize in the presence of an acid or base; racemization at any of the stages of making Melphalan is one of the most serious problems in the manufacture of Melphalan.
It is the prime objective of this invention to provide a chemical process of making optically pure Melphalan involving steps that does not cause racemization.